Reply:
Authors: Peter Ferenci
Journal: Hepatology (2008)

We thank Dr. Anghemo and his colleagues for their comments regarding our randomized controlled trial that compared ribavirin dosages of 400 and 800 mg/day in combination with peginterferon alfa-2a given for 24 weeks in treatment-naive patients with hepatitis C virus (HCV) genotype 2 or 3 infection.1 As Anghemo and his colleagues correctly pointed out, no conclusions can be drawn from the few data shown in their letter. This is also unnecessary because, in addition to our study, two large randomized multicenter trials have compared high and low ribavirin dosage regimens in treatment-naive genotype 2/3 patients.2, 3 The seminal study by Hadziyannis et al.2 clearly showed that there was no statistically significant difference in sustained virologic response (SVR) rates between genotype 2/3 patients treated for 24 weeks with peginterferon alfa-2a in combination with a high (1000 or 1200 mg/day) or low (800 mg/day) ribavirin dosage (81% versus 84%, respectively). Importantly, the incidence of treatment-related serious adverse events, ribavirin dosage reductions, and decreases in the hemoglobin concentration to less than 100 g/L was higher in patients randomized to the high ribavirin dosage regimen.2 Jacobson et al.3 subsequently confirmed these results in a large randomized multicenter trial. There was no significant difference in SVR rates between patients treated with ribavirin at a dosage of 800 to 1400 mg/day (67.7%) or 800 mg/day (65.0%) in combination with peginterferon alfa-2b for 24 weeks.3 Thus, our study was the third randomized multicenter study of ribavirin dosage in genotype 2/3 patients treated for 24 weeks. Once again, there was no significant difference in SVR rates between the two dosage regimens. Moreover, the individual dose of ribavirin (mg/kg/day) had no impact on SVR (Fig. 1). Individual dose of ribavirin (mg/kg/day) versus the sustained virologic response (SVR), relapse (REL), and nonresponse (NR) rates. On the basis of three randomized trials, we see no need to use ribavirin doses greater than 800 mg/day in treatment-naïve patients with genotype 3, provided that the planned duration of treatment is 24 weeks. In addition to ribavirin dose, treatment duration is a key determinant of SVR. In a follow-up study, we investigated shortening the duration of peginterferon alfa-2a treatment to 16 weeks in combination with ribavirin at a dosage of either 400 or 800 mg/day. This study had to be stopped for ethical reasons after 100 patients had been recruited because the relapse rate in the low-dose group was 50%. The ACCELERATE trial subsequently demonstrated convincingly that an abbreviated 16-week regimen of peginterferon alfa-2a plus ribavirin 800 mg/day is less effective than a 24-week regimen.4 It is not clear that the use of higher dosages of ribavirin compensate for the inadequacy of treatment durations less than 24 weeks.5 A small proportion of genotype 3 patients appear to be treatment-resistant, as evidenced by detectable HCV RNA levels at week 4 of treatment. These individuals have higher relapse rates and lower SVR rates than patients who clear HCV RNA by week 4. At present, it is not possible to identify these patients before treatment is initiated. How best to manage these individuals is an as yet unanswered question. An ongoing randomized trial will determine whether prolonging treatment to 48 weeks is the key to curing HCV infection in these individuals. Peter Ferenci*, * Gastroenterology and Hepatology Department of Internal Medicine III Medical University of Vienna Vienna, Austria.